Farnesyltransferase inhibiting quinazolinones

ABSTRACT

This invention concerns compounds of formula                    
     the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R 1  and R 2  each independently are hydrogen, hydroxy, halo, cyano, C 1-6 alkyl, trihalomethyl, trihalomethoxy, C 2-6 alkenyl, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, aminoC 1-6 alkyloxy, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyloxy, Ar 1 , Ar 1 C 1-6 alkyl, Ar 1 oxy, Ar 1 C 1-6 alkyloxy; or when on adjacent positions R 1  and R 2  taken together may form a bivalent radical; R 3  and R 4  each independently are hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxy, Ar 1 oxy, C 1-6 alkylthio, di(C 1-6 alkyl)amino, trihalomethyl, trihalomethoxy; R 5  is hydrogen, halo, cyano, optionally substituted C 1-6 alkyl, C 1-6 alkyloxycarbonyl or Ar 1 ; or a radical of formula —OR 10 , —SR 10 , —NR 11 R 12 ; R 6  is an optionally substituted imidazolyl moiety; R 7  is hydrogen or C 1-6 alkyl provided that the dotted line does not represent a bond; R 8  is hydrogen, C 1-6 alkyl or Ar 2 CH 2  or Het 1 CH 2 ; R 9  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy or halo, or R 8  and R 9  taken together may form a bivalent radical; Ar 1  and Ar 2  are optionally substituted phenyl and Het 1  is optionally substituted pyridinyl; having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of PCT applicationPCT/EP98/02357, filed Apr. 17, 1998 which claims priority from EP PatentApplication No. 97.201.259.5, filed Apr. 25, 1997.

The present invention is concerned with novel quinazolinone derivatives,the preparation thereof, pharmaceutical compositions comprising saidnovel compounds and the use of these compounds as a medicine as well asmethods of treatment by administering said compounds.

Genetic research has led to the identification of a variety of genefamilies in which mutations can lead to the development of a widevariety of tumors. A particular group of genes, known as ras, have beenidentified in mammals, birds, insects, mollusks, plants, fungi andyeasts. The family of mammalian ras genes consists of three majormembers (“isoforms”): H-ras, K-ras and N-ras genes. These ras genes codefor highly related proteins generically known as p21^(ras). Thesep21^(ras) proteins comprise a family of proteins that regulate cellgrowth when bound to the inner surface of the plasma membrane. However,overproduction of p21^(ras) proteins, or mutations of said ras genesthereby coding for mutant or oncogenic forms of p21^(ras) proteins, leadto uncontrolled cell division. In order to regulate cell growth, the rasproteins need to be attached to the inner leaflet of the plasmamembranes. If mutated or oncogenic forms of p21^(ras), the p21^(ras)oncoproteins, become attached to plasma membranes, they provide a signalfor the transformation of normal cells to tumor cells and promote theiruncontrolled growth. To acquire this transforming potential, theprecursor of the p21^(ras) oncoprotein must undergo an enzymaticallycatalyzed farnesylation of the cysteine residue located in acarboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzyme thatcatalyzes this modification, farnesyl protein transferase, will preventthe membrane attachment of p21^(ras) and block the aberrant growth ofras-transformed tumors. Hence, it is generally accepted in the art thatfarnesyl transferase inhibitors can be very useful as anticancer agentsfor tumors in which ras contributes to transformation.

Since mutated or oncogenic forms of ras are frequently found in manyhuman cancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl transferase inhibitors can be very usefulagainst these types of cancer.

EP-0,371,564 discloses (1H-azol-1-ylmethyl) substituted quinoline,quinazoline and quinoxaline derivatives which suppress the plasmaelimination of retinoc acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex.

It has been found that the present novel compounds, all having a phenylsubstituent on the 4-position of the 2-quinazolinone-moiety bearing acarbon or nitrogen-linked imidazolyl moiety, show farnesyl proteintransferase inhibiting activity.

The present invention concerns compounds of formula

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar¹C₁₋₆alkyl, Ar¹oxy, Ar¹C₁₋₆alkyloxy,

R³ and R⁴ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar¹oxy, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, trihalomethylor trihalomethoxy;

R⁵ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar¹,Ar¹C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula

wherein

R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹, Ar¹C₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical for formula —Alk—OR¹³ or—Alk—NR¹⁴R¹⁵;

R¹¹ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;

R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar¹C₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,Ar¹ carbonyl, Ar¹C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula —Alk—OR¹³ or—Alk—NR¹⁴R¹⁵;

wherein

Alk is C₁₋₆alkanediyl;

R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr¹C₁₋₆alkyl;

R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;

R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar¹C₁₋₆alkyl;

R⁶ is a radical of formula

wherein

R¹⁶ is hydrogen, halo, Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

R¹⁷ is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

R⁷ is hydrogen or C₁₋₆alkyl provided that the dotted line does notrepresent a bond;

R⁸ is hydrogen, C₁₋₆alkyl or Ar²CH₂ or Het¹CH₂;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo; or

R⁸ and R⁹ taken together to form a bivalent radical of formula

Ar¹ is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl;

Ar² is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl; and

Het¹ is pyridinyl; pyridinyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₂alkyl defines methyl or ethyl;C₁₋₄alkyl includes C₁₋₂alkyl and the higher homologues thereof having 3to 4 carbon atoms such as, e.g. propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higherhomologues thereof having 5 to 6 carbon atoms such as, for example,pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C₂₋₆alkenyldefines straight and branched chain hydrocarbon radicals containing onedouble bond and having from 2 to 6 carbon atoms such as, for example,ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, and the like; C₁₋₆alkanediyl defines bivalentstraight and branched chained saturated hydrocarbon radicals having from1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and thebranched isomers thereof. The term “S(O)” refers to a sulfoxide and“S(O)₂” to a sulfon.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The compounds of formula (I) which have basic properties can beconverted in their pharmaceutically acceptable acid acid addition saltsby treating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; surfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

The term acid addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

In those compounds where the dotted line does not represent a bond, thenitrogen on the 3-position of the quinazolinone moiety allows for anextra bond, i.e. radical R⁷. In those compounds where the dotted linerepresents a bond, said radical R⁷ is absent.

Wherever R⁸ and R⁹ are taken together to form a bivalent radical offormula (c-4) or (c-5), the CH₂ moiety in said bivalent radical ispreferably connected to the nitrogen atom of the 2-quinazolinone moietyof the compounds of formula (I).

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid addition salts andall stereoisomeric forms.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

a) R¹ and R² are each independently selected from hydrogen, halo,C₁₋₆alkyl, C₁₋₆alkyloxy or trihalomethyl; in particular hydrogen, haloor C₁₋₄alkyl;

b) R³ and R⁴ are each independently selected from hydrogen, halo,C₁₋₆alkyl, C₁₋₆alkyloxy or trihalomethyl; in particular hydrogen, haloor C₁₋₄alkyl;

c) R⁵ is is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₆alkyl and R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl; in particular R⁵is hydrogen, hydroxy, halo, or amino;

d) R⁶ is a radical for formula (b-1) or (b-2) wherein R¹⁶ is hydrogen orC₁₋₆alkyl and R¹⁷ is C₁₋₆alkyl;

e) R⁷ is hydrogen or C₁₋₆alkyl in case the dotted line does notrepresent a bond;

f) R⁸ is hydrogen, C₁₋₆alkyl or Het¹CH₂;

g) R⁹ is hydrogen.

A particular group of compounds consists of those compounds of formula(I) wherein X is oxygen, R¹ and R² are each independently selected fromhydrogen, halo, C₁₋₄alkyl; R³ and R⁴ are each independently selectedfrom hydrogen, halo, C₁₋₄alkyl; R⁵ is hydrogen, hydroxy, halo or aamino; R⁶ is a radical of formula (b-1) or (b-2) wherein R¹⁶ is hydrogenor C₁₋₄alkyl and R¹⁷ is C₁₋₄alkyl; R⁷ is hydrogen or C₁₋₄alkyl in casethe dotted line does not represent a bond; R⁸ is hydrogen; C₁₋₄alkyl orHet¹CH₂; and R⁹ is hydrogen.

Preferred compounds are those compounds of formula (I) wherein X isoxygen, R¹ is 3-chloro, R² is hydrogen, R³ is 4-chloro, R⁴ is hydrogen,R⁵ is hydrogen, C₁₋₂alkyl, halo or amino; R⁶ is a radical of formula(b-1) or (b-2) wherein R¹⁶ is hydrogen and R¹⁷ is C₁₋₂alkyl; and R⁷ ishydrogen or C₁₋₂alkyl in case the dotted line does not represent a bond;R⁸ is hydrogen, C₁₋₂alkyl or Het¹CH₂; and R⁹ is hydrogen.

The most preferred compounds of formula (I) are

6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinazolinone;and

6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-3,4-dihydro-1,3-dimethyl-2(1H)-quinazolinone;the stereoisomeric forms and the pharmaceutically acceptable acidaddition salts thereof.

The compounds of formula (I) wherein R⁶ is a radical of formula (b-1),represented by compounds of formula (I-a), can generally be prepared byN-alkylating an intermediate of formula (III), with an intermediate offormula (II), wherein W is an appropriate leaving group such as, forexample, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy. Thereaction can be performed in a reaction-inert solvent such as, forexample, acetonitrile, and optionally in the presence of a suitable basesuch as, for example, sodium carbonate, potassium carbonate ortriethylamine. Stirring may enhance the rate of the reaction. Thereaction may conveniently be carried out at a temperature rangingbetween room temperature and reflux temperature.

Also, compounds of formula (I-a) can be prepared by reacting anintermediate of formula (IV) with an intermediate of formula (V),wherein Y is carbon or sulfur, such as, for example, a1,1′-carbonyldiimidazole.

Said reaction may conveniently be conducted in a reaction-inert solvent,such as, e.g. tetrahydrofuran, optionally in the presence of a base,such as sodium hydride, and at a temperature ranging between roomtemperature and the reflux temperature of the reaction mixture.

The compounds of formula (I) wherein R⁶ represents a radical of formula(b-2), R⁵ is hydroxy and R¹⁷ is C₁₋₆alkyl, said compounds being referredto as compounds of formula (I-b-1) may be prepared by reacting anintermediate ketone of formula (VI) with an intermediate of formula(III-1). Said reaction requires the presence of a suitable strong base,such as, for example, butyl lithium in an appropriate solvent, such as,for example, tetrahydrofuran, and the presence of an appropriatesilanederivative, such as, for example, triethylchlorosilane. During thework-up procedure an intermediate silane derivative is hydrolyzed. Otherprocedures with protective groups analogous to silanederivatives canalso be applied.

Also, the compounds of formula (I), wherein R⁶ is a radical of formula(b-2), R⁵ is hydroxy and R¹⁷ is hydrogen, said compounds being referredto as compounds of formula (I-b-2) may be prepared by reacting anintermediate ketone of formula (VI) with an intermediate of formula(III-2), wherein PG is a protective group such as, for example, asulfonyl group, e.g. a dimethylamino sulfonyl group, which can beremoved after the addition reaction. Said reaction is conductedanalogously as for the preparation of compounds of formula (I-b-1),followed by removal of the protecting group PG, yielding compounds offormula (I-b-2).

Compounds of formula (I-c), defined as compounds of formula (I) whereinR⁷ is hydrogen and the dotted line does not represent a bond, can beconverted into compounds of formula (I-d), defined as compounds offormula (I) wherein the dotted line represents a bond, by art-knownoxidation procedures such as, e.g. oxidation with MnO₂ in areaction-inert solvent, e.g. dichloromethane.

Conversely, compounds of formula (I-d) can be converted to compounds offormula (I-c) using art-known reduction procedures such as, e.g.treatment with sodiumborohydride in a suitable solvent, e.g. methanol.

Also, compounds of formula (I-c) can be converted to compounds offormula (I-c-1) by treating compounds (I-c) with a reagent of formulaR⁷-W¹, wherein W¹ is an appropriate leaving group such as, for example,chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy, using theabove-described N-alkylation procedure.

The compounds of formula (I-b) can be converted to compounds of formula(I-e), defined as a compound of formula (I) wherein R⁶ is a radical offormula (b-2) and R⁵ is hydrogen, by submitting the compounds of formula(I-b) to appropriate reducing conditions, such as, e.g. stirring inacetic acid in the presence of formamide.

Further, compounds of formula (I-b) can be converted to compounds offormula (I-f) wherein R⁵ is halo, be reacting the compounds of formula(I-b) with a suitable halogenating agent, such as, e.g. thionyl chlorideor phosphorus tribromide. Successively, the compounds of formula (I-f)can be treated with a reagent of formula H—NR¹¹R¹² in a reaction-inertsolvent, thereby yielding compounds of formula (I-g).

A compound of formula (I-i), defined as a compound of formula (I)wherein X is sulfur, may be prepared by reacting the correspondingcompound of formula (I-h), defined as a compound of formula (I) whereinX is oxygen, with a reagent like phosphorus pentasulfide or Lawesson'sreagent in a suitable solvent such as, for example, pyridine.

An intermediate of formula (II-a), being an intermediate of formula (II)wherein X is oxygen and R⁷ and R⁸ are hydrogen, can be prepared startingfrom an intermediate of formula (VII). Said intermediate (VII), whereinn is 2 or 3, is conveniently prepared by protecting the correspondingart-known ketone as a ketal. An intermediate of formula (VII) is reactedwith an intermediate of formula (VIII) in the presence of a base such assodium hydroxide, in an appropriate solvent, e.g. methanol. The thusobtained intermediate of formula (IX) undergoes ring opening of theisoxazole moiety by hydrogenation of intermediate (IX) in the presenceof a suitable catalyst such as, e.g. Raney Nickel. Subsequent acylationwith a reactive carboxylic acid derivative, e.g. trichloroacetylchloride or trifluoroacetyl chloride, yields an intermediate of formula(X), which undergoes ring closure in the presence of an ammonium salt,e.g. ammonium acetate, and an appropriate base such as, e.g.hexamethylphosphorous triamide (HMPT). Intermediates of formula (X) aresubmitted to acidic conditions and subsequently treated with art-knownreducing agents such as, e.g. sodium borohydride, yielding intermediatesof formula (XII). The hydroxy group of intermediates of formula (XII) isconverted to a leaving group W by treating intermediates (XII) with asuitable reagent such as, e.g. methanesulfonyloxy chloride, or ahalogenating reagent such as, e.g. POCl₃ or SOCl₂, yieldingintermediates of formula (II-a).

Intermediates for formula (II-b), defined as intermediates of formula(II) wherein X is O and R⁷ is hydrogen, can be prepared by reactingintermediates of formula (XI) with R⁸-W¹, wherein W¹ is a suitableleaving group such as, e.g. chloro, bromo, methanesulfonyloxy orbenzenesulfonyloxy; using the above-described N-alkylation procedure.Subsequent reduction with e.g. sodiumborohydride in a suitable solvent,e.g. methanol, and hydrolysis under acidic conditions, yieldsintermediates of formula (XIV). Convertion of the hydroxy group ofintermediates (XIV) into leaving group W, e.g. by treatment withmethanesulfonyloxy chloride or a halogenating reagent such as, e.g.SOCl₂, POCl₃, gives intermediates of formula (II-b).

Intermediates of formula (VI-a), defined as intermediates of formula(VI) wherein X is O and the dotted line does not represent a bond, canbe prepared by submitting intermediates of formula (XIII) to art-knownreduction procedures, such as, e.g. treatment with sodium borohydride ina reaction-inert solvent e.g. methanol, thereby yielding intermediatesof formula (XV). Intermediates (XV) are N-alkylated with R⁷-W¹, whereinW¹ is a leaving group as above-described, and subsequently hydrolysedunder acidic conditions to intermediates of formula (VI-a).

Also, intermediates of formula (VI-b), defined as intermediates offormula (VI) wherein X is O and the dotted line represents a bond, canbe prepared by hydrolysis of the intermediate of formula (IX) with anacid, such as for example, TiCl₃, in the presence of water. Subsequentacylation with a reactive carboxylic acid derivative, such as, e.g.trichloroacetyl chloride, yields an intermediate of formula (XVII),which undergoes ring closure in the presence of an ammonium salt, e.g.ammonium acetate, and an appropriate base such as, e.g.hexamethylphosphorous triamide (HMPT), thereby yielding an intermediateof formula (VI-b).

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Specific stereoisomers can be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of of tumors in vivo by a direct effect on tumor cell growthbut also indirectly, i.e. by facilitating tumor-induced angiogenesis(Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence,pharmacologically targetting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma), pancreaticcancers (e.g. pancreatic carcinoma such as, for example exocrinepancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, suchas, for example, colon adenocarcinoma and colon adenoma), hematopoietictumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-celllymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas andrhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas,gliomas, benign tumor of the skin (e.g. keratoacanthomas), breastcarcinoma, kidney carcinoma, ovary carcinoma, bladder carcinoma andepidermal carcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes, i.e. the ras geneitself is not activated by mutation to an oncogenic form, with saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneurofibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes may be inhibited by thecompounds of this invention.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove mentioned conditions.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, to aidsolubility for example, may be included. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeleterious effect to the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. It isespecially advantageous to formulate the aforementioned pharmaceuticalcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used in the specification andclaims herein refers to physically discrete units suitable as unitarydosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.01 mg/kg to 100mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.05 to 500 mg, and in particular 0.1 mg to 200 mg of activeingredient per unit dosage form.

The following examples are provided for purposes of illustration.

EXPERIMENTAL PART

A. Preparation of the Intermediates

Hereinafter “THF” means tetrahydrofuran, “DIPE” means diisopropylether,“DCM” means dichloromethane, “DMF” means N,N-dimethylformamide and “ACN”means acetonitrile.

Of some compounds of formula (I) the absolute stereochemicalconfiguration was not experimentally determined. In those cases thestereochemically isomeric form which was first isolated is designated as“A” and the second as “B”, without further reference to the actualstereochemical configuration.

EXAMPLE A.1

a) A mixture of (4-chlorophenyl)(4-nitrophenyl)methanone (0.0382 mol),1,2-ethanediol (0.0764 mol) and 4-methylbenzenesulfonic acid monohydrate96% (0.19 mol) in methylbenzene (150 ml) was stirred and refluxed in aDean Stark apparatus for 24 hours. The mixture was washed with K₂CO₃(10%) and then with water. The organic layer was dried, filtered off andevaporated. The product was used without further purification, yielding11.42 g (98%) of 2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane(interm. 1).

b) Sodium hydroxide (0.818 mol) and then 3-chlorobenzenacetonitrile(0.294 mol) were added to a solution of intermediate (1) (0.164 mol) inmethanol (200 ml) and the mixture was stirred at room temperatureovernight. The mixture was quenched with water and extracted with DCM.The organic layer was dried, filtered off and evaporated till dryness.The residue was recrystallized from DIPE, yielding 47.3 g (70%) of3-(3-chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2,1-benzisoxazole(interm. 2).

c) Intermediate (2) (0.0381 mol) in methanol (200 ml) was hydrogenatedwith Raney nickel (15 g) as a catalyst at room temperature over a 5 hourperiod under a 3×10⁵ Pa (3 bar) pressure in a Parr apparatus. Afteruptake of hydrogen, the catalyst was filtered off and the filtrate wasevaporated till dryness. The product was used without furtherpurification, yielding 15.7 g of[2-amino-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-phenyl](3-chlorophenyl)methanone(interm. 3).

d) A mixture of intermediate (3) (0.098 mol) in DCM (400 ml) was stirredat 5-10° C. Trichloroacetyl chloride (0.12 mol) was added dropwise, overa 15-minutes period, at a temperature between 5-10° C. Triethylamine(0.12 mol) was added dropwise, over a 20-minutes period, at 5-10° C. Thereaction mixture was stirred for one hour at 5-10° C. Water (250 ml) wasadded and stirring was continued for 5 minutes. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas purified over silica gel on a glass filter (eluent: DCM). Thedesired fractions were collected and the solvent was evaporated. Theresidue was stirred in ACN, filtered off and dried, yielding 46.5 g(85%) oftrichloro-N-[2-(3-chlorophenyl)-4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]acetamide(interm. 4).

e) A mixture of intermediate (4) (0.078 mol) and ammonium acetate (0.156mol) in hexamethylphosphorous triamide (HMPT) (300 ml) was stirred for 3hours at 100° C. The reaction mixture was cooled, poured out into icewater (1500 ml) and precipitation resulted. The precipitate was filteredoff, and washed with water. The product was dissolved in DCM. Theorganic layer was isolated, dried, filtered and the solvent evaporated.The residue was purified three times over silica gel on a glass filter(eluent: CH₂Cl₂/CH₃OH 97/3, then 95/5). The desired fractions werecollected and the solvent was evaporated. The residue was stirred inrefluxing isopropanol (200 ml). The mixture was cooled and the resultingprecipitate was filtered off, washed with DIPE, and dried, yielding 26 g(76%) of 4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2yl]-2(1H)-quinazolinone (interm. 5, mp. 219.5° C.).

f) A mixture of intermediate (5) (0.052 mol) in hydrochloric acid, 3N(250 ml) and methanol (250 ml) was stirred and refluxed for 2 hours. Thereaction mixture was cooled. Water (250 ml) was added and the resultingprecipitate was filtered off, washed with water, isopropanol and DIPE,then dried, yielding 19.4 g (94.4%) of6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinazolinone (interm. 6;mp. 256.4° C.).

g) A mixture of intermediate (6) (0.005 mol) in methanol (50 ml) wasstirred and cooled on an ice-bath (5-10° C.). Sodium borohydride (0.007mol) was added portionwise over a 15-minutes period (first, dissolutionresulted; after 15 minutes precipitation started). The mixture wasstirred for 1 hour at room temperature. The mixture was acidified with 1N HCl. The precipitate was filtered off, washed with DIPE, then dried,yielding 1.6 g (80%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxymethyl]-3,4-dihydro-2(1H)-quinazolinone(interm. 7; mp. 231.4° C.).

h) A mixture of intermediate (7) (0.013 mol) in DCM (60 ml) was stirredat room temperature. Thionyl chloride (0.065 mol) was added dropwiseover a 15-minutes period. The reaction mixture was stirred for 3 hoursat room temperature. Dissolution resulted. The solvent was evaporated.Toluene was added and azeotroped on the rotary evaporator, yielding 5.4g of(±)-6-[chloro(4-chlorophenyl)methyl]-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone(interm. 8).

Example A.2

a) A mixture of intermediate (5) (0.0455 mol) in DMF (500 ml) wasstirred at room temperature, under N₂ flow. A dispersion of sodiumhydride (50%) in mineral oil (0.0455 mol) was added portionwise. Thereaction mixture was stirred until gas evolution stopped. Iodomethane(0.0455 mol) was added dropwise and the resulting reaction mixture wasstirred for 14 hours at room temperature. The solvent was evaporated.Toulene was added and azeotroped on the rotary evaporator. The crude oilwas stirred in DCM (300 ml), washed with water (2×250 ml), dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: DCM). The desiredfractions were collected and the solvent was evaporated, yielding 16.7 g(80%) of4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-1-methyl-2(1H)-quinazolinone(interm. 9).

b) A mixture of intermediate (9) (0.037 mol) in methanol (300 ml) wasstirred at room temperature. Hydrochloric acid (0.75 mol) was addeddropwise and the resulting reaction mixture was stirred and refluxed forone hour, then cooled to room temperature and extracted with DCM (2×250ml). The separated organic layer dried, filtered and the solvent wasevaporated. The residue was triturated in PIPE. The precipitate wasfiltered off, washed with DIPE (100 ml) and dried (vacuum, 60° C.; 14hours), yielding 12.6 g (83%) of6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinazolinone(interm. 10).

Example A.3

a) A suspension of intermediate (10) (0.031 mol) in methanol (150 ml)was stirred at room temperature. Sodium borohydride (0.062 mol) wasadded portionwise (maximal temperature rise of 5° C.). The reactionmixture was stirred for 2 hours at room temperature. The precipitate wasfiltered off, washed with water (50 ml), isopropanol (100 ml) and DIPE(100 ml), then dried (vacuum; 50° C.), yielding 11.5 g (90%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxymethyl]-3,4-dihydro-1-methyl-2(1H)-quinazolinone(interm. 11)

b) DCM (0.0556 mol) was added dropwise to a mixture of intermediate (11)(0.028 mol) in DCM (100 ml). The reaction mixture was stirred andrefluxed for 2 hours. The solvent was evaporated. Toulene was added andazeotroped on the rotary evaporator, yielding 12.09 g of(±)-6-[chloro(4-chlorophenyl)methyl]-4-(3-chlorophenyl)-3,4-dihydro-1-methyl-2(1H)-quinazolinone(interm. 12).

Example A.4

a) A solution of intermediate (9) (0.0122 mol) in methanol (50 ml) wascooled to 5° C. Sodium borohydride (0.0122 mol) was added portionwiseand the mixture was allowed to stand at 5° C. for 30 minutes. Themixture was poured out on ice-water. The precipitate was filtered off,washed with water and dried, yielding 5.4 g (98%) of(±)-4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3,4-dihydro-1-methyl-2(1H)-quinazolinone(interm. 13).

b) Intermediate (13) (0.0107 mol) was dissolved in DMF (50 ml) at 0° C.under N₂ flow. A dispersion of sodium hydride (80%) in mineral oil(0.013 mol) was added and the mixture was allowed to stand at 0° C. for30 minutes. Iodomethane (0.0215 mol) was added dropwise and the mixturewas allowed to stand at 0° C. for 1 hour. The mixture was poured out onice-water. The precipitate was filtered off, washed with water and takenup in DCM. The organic layer was dried, filtered and the solvent wasevaporated, yielding 6.2 g of(±)-4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3,4-dihydro-1,3-dimethyl-2(1H)-quinazolinone(interm. 14).

c) A mixture of intermediate (14) (0.0259 mol) in acetic acid (75 ml),water (20 ml) and THF (10 ml) was stirred and refluxed overnight, andthe solvent was evaporated. The residue was taken up in DCM and washedwith K₂CO₃ (10%). The organic layer was decanted, dried, filtered, andthe solvent was evaporated, yielding 11 g (100%) of product. A samplewas crystallized from 2-propanone/DIPE. The precipitate was filtered offand dried, yielding 1.5 g of(±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-1,3-dimethyl-2(1H)-quinazolinone(interm. 15).

Example A.5

a) A mixture of intermediate (5) (0.0175 mol) in DMF (80 ml) was cooledon an ice bath under nitrogen flow. Sodium hydride (80% in oil, 0.0228mol) was added portionwise and the mixture was stirred at a lowtemperature for 30 minutes, then at room temperature for 1 hour. Themixture was cooled to 5° C. and chloromethyl ethyl ether (0.0228 mol)was added. The mixture was stirred at a low temperature for 30 minutesand then hydrolized. The precipitate was filtered off, washed withwater, taken up in DCM, dried, filtered, and the solvent was evaporatedtill dryness. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1), yielding 2.9 g (33.3%)of4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-1-(ethoxymethyl)-2(1H)-quinazolinone(interm. 16).

b) A mixture of intermediate (16) (0.0058 mol) in methanol (50 ml) wascooled on an ice bath. Sodium borohydride (0.0058 mol) was addedportionwise. The mixture was stirred at a low temperature for 30minutes, then poured out into ice water and extracted with DCM. Theorganic layer was separated, dried, filtered, and the solvent wasevaporated till dryness, yielding 2.9 g (100%) of(±)-4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-1-(ethoxymethyl)-3,4-dihydro-2(1H)-quinazolinone(interm. 17).

c) A mixture of intermediate (17) (0.0058 mol) in DMF (30 ml) was cooledon an ice bath under nitrogen flow. Sodium hydride (80% in oil, 0.007mol) was added and the mixture was stirred at a low temperature for 30minutes. Methyl iodide (0.007 mol) was added dropwise. The mixture wasstirred at a low temperature for 1 hour, then allowed to warm to roomtemperature, hydrolized and water was added. The precipitate wasfiltered off, washed with water, taken up in DCM, dried, filtered, andthe solvent was evaporated till dryness, yielding 3 g (100%) of(±)-4-(3-chlorophenyl)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-1-(ethoxymethyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone(interm. 18).

d) A mixture of intermediate (18) (0.0058 mol) in HCl (30 ml) and THF(30 ml) was stirred and refluxed overnight, cooled by adding ice,basified with NH₃(aq.) and extracted with DCM. The organic layer wasseparated, dried, filtered and the solvent was evaporated till dryness.The residue was taken up in 2-propanone and DIPE. The precipitate wasfiltered off, washed and dried, yielding 2.2 g (91.6%) of(±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro3-methyl-2(1H)-quinazolinone(interm. 19).

e) Sodium borohydride (0.0053 mol) was added to a mixture ofintermediate (19) (0.0053 mol) in methanol (20 ml) and THF (20 ml),previously cooled on an ice bath (5° C.). The mixture was stirred at 5°C. for 30 minutes, poured out into ice water and extracted with DCM. Theorganic layer was separated, dried, filtered and the solvent wasevaporated till dryness, yielding 2.2 g (100%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxymethyl]-3,4-dihydro-3-methyl-2(1H)-quinazolinone(interm. 20).

f) Thionyl chloride (10 ml) was added dropwise to a mixture ofintermediate (20) (0.005 mol) in DCM (50 ml), previously cooled on anice bath (5° C.). The mixture was stirred at room temperature for 1night. The solvent was evaporated till dryness. The product was usedwithout further purification, yielding quantitatively(±)-6-[chloro(4-chlorophenyl)methyl]-4-(3-chlorophenyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone(interm. 21).

B. Preparation of the Final Products

Example B.1

A mixture of intermediate (8) (0.013 mol), imidazole (0.039 mol) andpotassium carbonate (0.04 mol) in ACN (75 ml) was stirred and refluxedfor 3 hours. The solvent was evaporated. The residue was stirred inwater and this mixture was extracted with DCM. The separated organiclayer was dried, filtered and the solvent evaporated. The residue waspurified over silica gel on a glass filter (eluent: CH₂Cl₂/CH₃OH 95/5).The desired fractions were collected and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/(CH₃OH/NH₃) 95/2.5/2.5). The pure fractions were collectedand the solvent was evaporated. The residue was stirred in diethyl ether(50 ml), filtered off and dried, yielding 2.6 g (44.5%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-3,4-dihydro-2(1H)-quinazolinone(comp. 8); mp. 177.1° C.

Example B.2

A mixture of 1-methylimidazole (0.073 mol) in the THF (110 ml) wascooled to −70° C. under N₂ flow. A solution of n-butyllithium in hexane(1.6M) (45.6 ml) was added dropwise. The mixture was stirred at −70° C.for 30 minutes. Chlorotriethylsilane (0.073 mol) was added. The mixturewas allowed to warm slowly to room temperature and then cooled to −70°C. A solution of n-butyllithium in hexane (1.6M) (45.6 ml) was addeddropwise. The mixture was stirred at −70° C. for 1 hour, then brought to−15° C. and cooled to −70° C. A mixture of intermediate (10) (0.061 mol)in THF (100 ml) was added. The mixture was stirred at −70° C. for 30minutes, then brought to 0° C., hydrolized, extracted with ethyl acetateand decanted. The organic layer was dried, filtered and the solvent wasevaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5),yielding 9.5 g of product. The product was recrystallized from2-propanone/ACN. The precipitate was filtered off, washed with diethylether and dried, yielding 2 g of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinazolinonemonohydrate (comp. 4).

Example B.3

A mixture of compound (8) (0.0045 mol) and manganese(IV) oxide (0.05mol) in DCM (50 ml) was stirred for 18 hours at room temperature. Themixture was filtered over dicalite. The dicalite was washed withCH₂Cl₂/CH₃OH 90/10. The filtrate was evaporated. The residue waspurified over silica gel on a glass filter (eluent: CH₂Cl₂/CH₃OH 95/5).The desired fractions were collected and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 95/5) and recrystallized from ACN (25 ml). The precipitatewas filtered off, washed with DIPE, and dried, yielding 1 g (50%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-2(1H)-quinazolinone(comp. 1; mp. 255.1° C.).

Example B.4

Sodium borohydride (0.003 mol) was added portionwise at 5° C. to amixture of compound (4) (0.003 mol) in methanol (30 ml). The mixture wasstirred at 5° C. for 30 minutes, then hydrolyzed, extracted with DCM anddecanted. The organic layer was dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom diethyl ether. The precipitate was filtered off and dried, yielding1 g(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl)-1H-imidazol-5-yl)methyl]-3,4-dihydro-1-methyl-2(1H)-quinazolinone(comp. 13).

Example B.5

A dispersion of sodium hydride in mineral oil (60%)(0.0047 mol) wasadded portionwise to a mixture of compound (9) (0.0043 mol) in DMF (40ml) under N₂ flow. The mixture was stirred for 30 minutes at roomtemperature. A solution of iodomethane (0.0047 mol) in DMF (10 ml) wasadded dropwise and the resulting reaction mixture was stirred overnightat room temperature. The reaction mixture was poured out into water (200ml) and this mixture was extracted with toluene (3×100 ml). Theseparated organic layer was dried, filtered and the solvent evaporated.The residue was purified by column chromatography over silica gel(eluent: ethyl acetate/CH₃OH/(CH₃OH/NH₃) 90/5/5). The pure fractionswere collected and the solvent was evaporated. This fraction wasrepurified by column chromatorgraphy over silica gel (eluent:CH₂Cl₂/CH₃OH 100/0, upgrading over 20 minutes to 90/10; 125 ml/min). Thepure fractions were collected and the solvent was evaporated, yielding0.370 g (18%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-3,4-dihydro-1,3-dimethyl-2(1H-quinazolinone(comp. 10).

Example B.6

A dispersion of sodium hydride in mineral oil (60%)(0.01122 mol) wasadded portionwise to a mixture of compound (1) (0.0051 mol) in DMF (25ml) under N₂ flow. The mixture was stirred for 30 minutes at roomtemperature. A solution of 4-(chloromethyl)pyridine hydrochloride(0.00561 mol) in DMF (5 ml) was added dropwise and the resultingreaction mixture was stirred over the weekend at room temperature. Thereaction mixture was poured out into water and this mixture wasextracted with toluene. The separated organic layer was dried, filteredand the solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/(CH₃OH/NH₃)90/5/5). The desired fractions were collected and the solvent wasevaporated. This fraction was repurified by high-performance liquidchromatorgraphy over Kromasil RP-18 (100 Å, 10 μm, 5 cm DAC; eluent:(0.5% NH₄OAc in H₂O)/CH₃OH/CH₃CN 47/25/28 v/v). The pure fractions werecollected and the organic solvent was evaporated. The aqueous residuewas extracted with DCM. The separated organic layer was dried, filtered,and the solvent evaporated, yielding 0.900 g (32.8%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-1-(4-pyridinylmethyl)-2(1H-quinazolinone(comp. 3; mp. 61.4° C.).

Example B.7

A mixture of compound (4) (0.0069 mol) in formamide (34 ml) and aceticacid (68 ml) was stirred at 160° C. for 24 hours, then poured out intoice water and alkalised with a concentrated NH₃ (aq.) solution. Theprecipitate was filtered off, washed with water and taken up in DCM. Theorganic layer was separated, dried, filtered and the solvent wasevaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2).The pure fractions were collected and the solvent was evaporated. Theresidue was crystallized from 2-propanone/DIPE. The precipitate wasfiltered off and dried, yielding 0.85 g of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-3,4-dihydro-1-methyl-2(1H-quinazolinone(comp. 14).

Example B.8

Compound (4) (0.01 mol) was added at a low temperature to thionylchloride (50 ml). The mixture was stirred at 40° C. for 2 hours. Thesolvent was evaporated till dryness. The product was used withoutfurther purification, yielding 5.46 g of(±)-6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H-quinazolinonemonohydrochloride (comp. 6).

Example B.9

Ammonium hydroxide (50 ml) was cooled to 5° C. A solution of compound(6) (0.01 mol) in THF (50 ml) was added. The mixture was stirred at roomtemperature for 2 hours, then at 60° C. for 30 minutes and cooled. Ethylacetate was added. The mixture was decanted. The organic layer wasdried, filtered and the solvent was evaporated till dryness. The residuewas purified by column chromatography over silica gel (eluent:toulene/isopropanol/NH₄OH 75/25/2). The pure fractions were collectedand the solvent was evaporated. The residue was crystallized from DCMand diethyl ether. The precipitate was filtered off and dried, yielding1.1 g of(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H-quinazolinone(comp. 7).

Example B.10

a) A mixture of interm. (21) (0.0146 mol), 2-phenylimidazole (0.0219mol) and potassium carbonate (0.0438 mol) in ACN (80 ml) was stirred andrefluxed for 4 hours. The solvent was evaporated till dryness. Theresidue was taken up in DCM and water. The organic layer was separated,dried, filtered and the solvent was evaporated till dryness. The productwas used without further purification, yielding a mixture of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-1-yl)methyl]-2-methoxyquinazoline(interm. 22) and(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-4-yl)methyl]-2-methoxyquinazoline(interm. 23).

b) A mixture of intermediates (22) and (23) (0.0146 mol) in HCl (3 N,100 ml) and THF (100 ml) was stirred and refluxed for 3 hours, thenpoured out into ice water and extracted with ethyl acetate. The organiclayer was separated, dried, filtered and the solvent was evaporated tilldryness. The residue was purified by column chromatorgraphy over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5). Two pure fractions werecollected and their solvents were evaporated. The first fraction wascrystallized from ACN, 2-propanone and DIPE, yielding 1.2 g (15.8%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-1-yl)methyl]-2(1H-quinazolinone(comp. 19, mp. 170° C.). The second fraction was dissolved in2-propanone and DIPE and converted into the ethanedioic acid salt (1:1),yielding 0.8 g (8.7%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-4-yl)methyl]-2(1H)quinazolinoneethanedioate(1:1).monohydrate (comp. 20, mp. 197° C.).

Tables F-1 to F-4 list the compounds that were prepared according to oneof the above Examples.

TABLE F-1

Co. Ex. No. No. R¹ R³ R⁵ R⁸ R¹⁶ Physical data 1 B.3 3-Cl 4-Cl H H H mp.255.1° C. 2 B.3 3-Cl 4-Cl H CH₃— H mp. 123.3° C. 3 B.6 3-Cl 4-Cl H

H mp. 61.4° C. 19 B.10 3-Cl 4-Cl H H 2-phenyl mp. 170° C.

TABLE F-2

Co. Ex. No. No. R¹ R³ R⁵ R⁸ Physical data 4 B.2 3-Cl 4-Cl OH CH₃ .H₂O(1:1) 5 B.3 3-Cl 4-Cl H CH₃ .ethanedioate (1:1).H₂O (1:2) 6 B.8 3-Cl4-Cl Cl CH₃ .HCl (1:1) 7 B.9 3-Cl 4-Cl NH₂ CH₃ —

TABLE F-3

Co. Ex. No. No. R¹ R³ R⁵ R⁷ R⁸ R¹⁶ Physical data 8 B.1 3-Cl 4-Cl H H H Hmp. 177.1° C. 9 B.1 3-Cl 4-Cl H H CH₃ H mp. 111.5° C. 10 B.5 3-Cl 4-Cl HCH₃ CH₃ H — 11 B.5 3-Cl 4-Cl H CH₂CH₃ CH₃ H mp. 115.8° C. 18 B.1 3-Cl4-Cl H CH₃ H 2-phenyl mp. 236° C.

TABLE F-4

Co. Ex. No. No. R¹ R³ R⁵ R⁷ R⁸ Physical data 12 B.2 3-Cl 4-Cl OH CH₃ CH₃— 13 B.4 3-Cl 4-Cl OH H CH₃ — 14 B.7 3-Cl 4-Cl H H CH₃ — 15 B.7 3-Cl4-Cl H CH₃ CH₃ — 16 B.8 3-Cl 4-Cl Cl CH₃ CH₃ .HCl (1:1) 17 B.9 3-Cl 4-ClNH₂ CH₃ CH₃ (A)

C. Pharmacological Example

Example C.1

“Ras-Transformed Cell Phenotype Reversion Assay”

Insertion of activated oncogenes such as the mutant ras gene into mouseNIH 3T3 cells converts the cells to a transformed phenotype. The cellsbecome tumorigenic, display anchorage independent growth in semi-solidmedium and lose contact inhibition. Loss of contact inhibition producescell cultures which no longer form uniform monolayers. Rather, the cellspile up into multicellular nodules and grow to very high saturationdensities in plastic tissue culture dishes. Agents such as proteinfarnesyl transferase inhibitors which revert the ras transformedphenotype restore the uniform monolayer growth pattern to cells inculture. This reversion is easily monitored by counting the number ofcells in tissue culture plates. Transformed cells will achieve highercell numbers than cells which have reverted to an untransformedphenotype. Compounds which revert the transformed phenotype shouldproduce antitumor effects in tumors bearing ras gene mutations.

Method

Compounds are screened in tissue culture in NIH 3T3 cells transformed bythe T24 activated human H-ras gene. Cells are seeded at an initialdensity of 200,000 cells per well (9.6 cm² surface area) in six-wellcluster tissue culture plates. Test compounds are immediately added to3.0 ml cell growth medium in a 3.0 μl volume of DMSO, with a finalconcentration of DMSO in the cell growth medium of 0.1%. The testcompounds are run at concentrations of 5, 10, 50, 100, and 500 nM alongwith a DMSO treated vehicle control. (In case a high activity isobserved at 5 nM, the test compound is tested at even lowerconcentrations.) The cells are allowed to proliferate for 72 hours. Thenthe cells are detached in 1.0 ml trypsin-EDTA cell dissociation mediumand counted on a Coulter particle counter.

Measurements

Cell numbers expressed as cells per well are measured using a CoulterParticle Counter. All cell counts were corrected for the initial cellinput density by subtracting 200,000. Control cell counts=[cell countsfrom cells incubated with DMSO vehicle−200,000] Test compound cellcounts=[cell counts from cells incubated with test compound−200,000].${{Test}\quad {compound}\quad \% \quad {inhibition}} = {\lbrack {1 - \frac{{test}\quad {compound}\quad {cell}\quad {counts}}{{control}\quad {cell}\quad {counts}}} \rbrack \times 100\quad {\%.}}$

Compounds 5, 7, 14 and 15 had an IC₅₀ less than 500 nM.

What is claimed is:
 1. A compound of formula (I)

a pharmaceutically acceptable acid addition salt or a stereochemicallyisomeric form thereof, wherein the dotted line represents an optionalbond; X is oxygen or sulfur; R¹ and R² each independently are hydrogen,hydroxy, halo, cyano, C₁₋₆alkyl, trihalomethyl, trihalomethoxy,C₂₋₆alkenyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, aminoC₁₋₆alkyloxy, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar¹C₁₋₆alkyl, Ar¹oxy,Ar¹C₁₋₆alkyloxy; R³ and R⁴ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, Ar¹oxy, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,trihalomethyl or trihalomethoxy; R⁵ is hydrogen, halo, C₁₋₆alkyl, cyano,haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar¹,Ar¹C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar¹C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of formula—Alk—OR¹³ or —Alk—NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₆alkyl, Ar¹ orAr¹C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar¹C₁₋₆alkyl,C₁₋₆alkylcarbonyl-C₁₋₆alkyl, Ar¹ carbonyl, Ar¹C₁₋₆alkylcarbonyl,aminocarbonylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula—Alk—OR¹³ or —Alk—NR¹⁴R¹⁵; wherein Alk is C₁₋₆alkanediyl; R¹³ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr¹C₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl; R¹⁵ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar¹C₁₋₆alkyl; R⁶ is aradical of formula

wherein R¹⁶ is hydrogen, halo, Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R¹⁷ is hydrogen, C₁₋₆alkyl ordi(C₁₋₄alkyl)aminosulfonyl; R⁷ is hydrogen or C₁₋₆alkyl provided thatthe dotted line does not represent a bond; R⁸ is hydrogen, C₁₋₆alkyl orAr²CH₂ or Het¹CH₂; R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo; orR⁸ and R⁹ taken together to form a bivalent radical of formula

Ar¹ is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl; Ar² is phenyl; or phenyl substituted with 1 or 2substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy or trifluoromethyl; and Het¹ is pyridinyl; pyridinylsubstituted with 1 or 2 substituents each independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl.
 2. A compoundaccording to claim 1 wherein R¹ and R² are each independently selectedfrom hydrogen, halo or C₁₋₄alkyl, R³ and R⁴ are each independentlyselected from hydrogen, halo or C₁₋₄alkyl, R⁵ is hydrogen, hydroxy, haloor a amino; R⁶ is a radical of formula (b-1) or (b-2) wherein R¹⁶ ishydrogen or C₁₋₄alkyl and R¹⁷ is C₁₋₄alkyl; R⁷ is hydrogen or C₁₋₄alkylin case the dotted line does not represent a bond; R⁸ is hydrogen;C₁₋₄alkyl or Het¹CH₂; and R⁹ is hydrogen.
 3. A compound according to anyof claim 1 wherein X is oxygen, R¹ is 3-chloro, R² is hydrogen, R³ is4-chloro, R⁴ is hydrogen, R⁵ is hydrogen, C₁₋₂alkyl, halo or amino; R⁶is a radical of formula (b-1) or (b-2) wherein R¹⁶ is hydrogen and R¹⁷is C₁₋₂alkyl; and R⁷ is hydrogen or C₁₋₂alkyl in case the dotted linedoes not represent a bond; R⁸ is hydrogen; C₁₋₂alkyl or Het¹CH₂; and R⁹is hydrogen.
 4. A compound according to claim 1 wherein the compound is6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinazolinone;or6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-3,4-dihydro-1,3-dimethyl-2(1H)-quinazolinone;a stereoisomeric form or a pharmaceutically acceptable acid additionsalt thereof.
 5. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and as active ingredient atherapeutically effective amount of a compound as described of claim 1.6. A compound of formula (XI)

an acid addition salt or a stereochemically isomeric form thereof,wherein n is 2 or 3 and R¹, R², R³, R⁴ and R⁹ are as defined in claim 1.7. A process for preparing a compound of formula (I) wherein a) anintermediate of formula (III) is N-alkylated with an intermediate offormula (II) in a reaction-inert solvent and, optionally in the presenceof a suitable base, yielding a compound of formula (I-a);

b) an intermediate of formula (IV) is reacted with a compound of formula(V), yielding a compound of formula (I-a);

c) an intermediate ketone of formula (VI) is reacted with anintermediate of formula (III-1) or (III-2) in the presence of a suitablestrong base and in the presence an appropriate silanederivative,optionally followed by removal of a protective group PG; yielding eithera compound of formula (I-b-1) or (I-b-2);

 wherein in the above reaction schemes the dotted line and the radicalsX, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁶ are as defined in claim 1and W is an appropriate leaving group; d) or, compounds of formula (I)are converted into each other following art-known transformationreactions; or if desired; a compound of formula (I) is converted into apharmaceutically acceptable acid addition salt, or conversely, an acidaddition salt of a compound of formula (I) is converted into a free baseform with alkali; and, if desired, preparing stereochemically isomericforms thereof.
 8. A process for preparing a compound of formula (XI) asclaimed in claim 6 wherein an intermediate of formula (X) is cyclized inthe presence of an ammonium salt and an appropriate base;

wherein in the above reaction scheme n is 2 or 3 and R¹, R², R³, R⁴ andR⁹ are as defined in claim 1; or, compounds of formula (XI) areconverted into each other following art-known transformation reactions;or if desired; a compound of formula (XI) is converted into apharmaceutically acceptable acid addition salt, or conversely, an acidaddition salt of a compound of formula (XI) is converted into a freebase form with alkali; and, if desired, preparing stereochemicallyisomeric forms thereof.
 9. A method for inhibiting the abnormal growthof cells in a mammal in need thereof comprising administering aneffective amount of a compound as claimed in claim
 1. 10. A method forinhibiting tumor growth in a mammal in need thereof comprisingadministering an effective amount of a compound as claimed in claim 1.11. A method for inhibiting the growth of tumors expressing an activatedras oncogene in a mammal in need thereof comprising administering acompound as claimed in claim
 1. 12. A method for inhibitingproliferative diseases wherein ras proteins are activated as a result ofoncogenic mutation in genes in a mammal in need thereof comprisingadministering a compound as claimed in claim 1.